How to relieve symptoms of eye surface discomfort using medical ice slurry

Abstract

This provides a method to alleviate symptoms of discomfort on the surface of the eye. [Solution] A method for relieving symptoms of discomfort on the surface of the eye is disclosed herein, the method comprising: applying a cold slurry topically adjacent to the limbus of the cornea of ​​a patient's eye, wherein the cold slurry comprises water and a coagulation point inhibitor, the topical application of the cold slurry is configured to cause some degree of paralysis of the cornea of ​​the eye for a period of time, and ocular sensation of the eye is restored after a period of time.

Description

[Technical Field]

[0001] Technical field The present invention generally relates to apparatus, systems, and methods for preparing and administering biomaterials such as cold slurries. More specifically, the present invention relates to systems and methods for administering a cold slurry to a subject to treat discomfort on the surface of the eye by inducing ocular hypoesthesia in a safe and effective manner. [Background technology]

[0002] background The cornea of ​​the eye is a transparent, avascular tissue measuring approximately 11-12 mm horizontally and 9-11 mm vertically. Sridhar, MS, Anatomy of cornea and ocular surface. Indian Journal of Ophthalmology, 66(2), 190-194 (February 2018). This is located on the outermost surface of the eye. It is located in front of the pupil and iris to refract light when it enters.

[0003] Innervation of the cornea begins in the brainstem, where a large sensory root branches off from the pons and attaches to the caudal subnucleus of the trigeminal spinal tract, located in the lateral part of the medulla. It can be kicked. From there, the trigeminal nerve divides into three divisions, one of which is the division for the eye. This root further divides into three branches, one of which is called the extensor pair, known as the nasocilioid nerve. This purely sensory nerve travels along the upper part of the orbital cavity and contributes to smaller branches to the cornea. Two divisions derived from this nerve are called the short ciliary nerve and the long ciliary nerve. The short ciliary nerve is known They pass through the rhizome, proceed to the ciliary ganglion, then emerge from the nucleus, penetrate the sclera, and enter the extrachoroidal space, where they can migrate to the cornea. (Belmonte, C., Tervo, TT, & Gallar, J.) (2011). CHAPTER 16 - Sensory Innervation of the Eye. Adler's Physiology of the Eye (Eleventh Edition, pp. 363-384). Elsevier Inc.

[0004] The extrachoroidal space is located between the sclera, the outermost layer of the eyeball, and the choroid, the layer through which numerous blood vessels that supply nutrients to the eye's structure pass. Approximately 8-10 short hairs pierce the sclera. The ciliary nerves are present, and once they enter the extrachoroidal space, they branch into approximately 15-20 segments. The long ciliary nerves, in particular, have over 50 branches that penetrate the sclera and then branch again within the extrachoroidal space. At the junction between the sclera and the cornea, the nerves lose their myelin sheath and continue as free nerve endings. These nerves receive sensory signals from the cornea. They collect these particles and send them in the reverse direction towards the brainstem. Belmonte, C., Tervo, TT, & Gallar, J. (2011). CHAPTER 16 - Sensory Innervation of the Eye. Adler's Physiology of the Eye (Eleventh Edition, pp. 363-384). Elsevier Inc. All the details of corneal innervation. However, this is not fully understood overall and may vary somewhat from patient to patient. There may be some contributions from other nerve fibers or some normal anatomical variations in the pathway of innervation.

[0005] Free nerve endings are located beneath the corneal epithelium, the anterior layer that protects the corneal structure, and often contribute to painful eye sensations. When a patient suffers from these symptoms, the condition is an ocular surface disease (OSD). This condition is also known as dry eye syndrome (DES). The causes of this condition are multifaceted. One important cause is the production of an insufficient amount of watery tears, which deprives the eye of hydration and lubrication. Other causes of ocular surface disease may include meibomian gland dysfunction or damage to the corneal epithelium.

[0006] These modifications to the properties of corneal afferent neurons, including altering the ocular dryness induction and centralizing corneal input, may have significant consequences for both regulating tearing and managing eye pain. McMonnies, CW, The potential role of neuropathic mechanisms in dry eye syndromes, Journal of Optometry, 10, 5-13 (2017). Importantly, some patients continue to experience pain on the surface of their eyes even after their surface has returned to a clinically normal appearance. This situation presents clinical challenges as the cause is thought to be a somatosensory dysfunction of corneal innervation that persists long after the original injury that stimulated the nerve.

[0007] Other causes of corneal discomfort include postoperative pain that may occur after optical corneal refractive surgery, a procedure used to treat refractive errors that requires the removal of corneal epithelium before excimer laser ablation is applied. Other surgical procedures that do not necessarily involve epithelial removal but where the epithelium experiences slow to moderate drying during the procedure can also cause corneal discomfort. Patients may also experience eye discomfort after eye trauma (e.g., corneal abrasion) and laser in-situ keratomileusis (LASIK) surgery.

[0008] There are three different types of nociceptive receptors that innervate the cornea. Twenty percent of corneal nociceptors are Aδ mechanoreceptors, which are rapidly transmitted by deterioration of the surface of the eye. It is the cause of sharp and painful stimuli. 70% of corneal nociceptors are polymodal, which are stimulated by corneal nerve damage, causing neuropathic pain and "reflex tearing". Levitt, A. E., et al., Chronic dry eye symptoms after LASIK: parallels and lessons to be learned from other persistent post-operative pain disorders, Molecular Pain, 11:21 (2015). The remaining 10% of corneal nociceptors are C-fiber cold receptors, which play a crucial role in maintaining basal tear secretion. These receptors are highly sensitive to temperature changes within the corneal tissue, and LASIK surgery causes evaporation of tears on the surface of the tear film, reducing the temperature by approximately 0.3°C per second, which can affect C-fiber signals . (Levitt et al., 2015).

[0009] Many mechanisms, such as dryness, previous surgery, dysfunction of the eyelid gland, or previous chemical irritation, can cause prominent clinical symptoms of OSD characterized by signs of eye irritation and symptoms featuring dryness, burns, or discomfort. Even after the initial injury to the mechanism has resolved, that is, after normal eye lubrication has been restored, patients may still report significant symptoms of discomfort on the eye surface, even though the eye surface of the patient has only minimal signs of the disease, suggesting components of hypersensitivity or allodynia. In fact, the literature reference notes that "the state of the eye surface alone is not sufficient to understand dry eye, and corneal somatosensory function... must be considered when evaluating patients with dry eye." Spierer O, Felix ER, McClel- lan AL, et al. Corneal mechanical thresholds negatively associate with dry eye severity. Invest Ophthalmol Vis Sci. 2015;56(13):7837-7844. Epub 2015 Oct 1. PMID: 26433806 with dry eye and ocular pain symptoms. Invest Ophthalmol Vis Sci.57:617-625 (2016). This situation presents a dilemma to the treating physician - the patient has remaining pain and discomfort (corneal somatic sensory dysfunction) along with a seemingly normal ocular surface. Additional lubrication and other therapies targeted at improving the ocular surface are, as expected, no longer of any help to these patients.

[0010] Dry eye syndrome / ocular surface disease, PRK, or LASIK surgery, or corneal somatic sensory dysfunction Current treatments for pain associated with are limited to either temporary value or have negative side effects. Dry eye syndrome is most commonly treated with warm compresses that target improved tear production or reduce inflammation, over-the-counter artificial tears, or prescription eye drops. Physicians may also recommend topical ocular lubricants, which are hygiene products that remove debris from under the eyelids. These methods work by softening meibum, an oily lipid-rich secretion from the meibomian glands, to assist in spreading tear production across the cornea. The limitations of these treatments are short-term relief and the need for continuous application. Lubricants or artificial tears may soothe irritation but do not actually address the cause of dry eye and may also contribute to an increase in debris that accumulates under the eyelids. Shen Lee, B., et al., Managing dry eye d isease and facilitating realistic patient expectations: A review and appraisal of current therapies, Clinical Ophthalmology, 14 119-126 (January 2020).

[0011] Regarding the management of postoperative pain for refractive corneal surgery and LASIK eye surgery Therefore, topical NSAIDs and soft bandage contact lenses are the most common treatments. NSAIDs prevent the production of prostaglandins, hormone-like substances associated with inflammation that occurs with corneal tissue damage. Pathak, AK, & Karacal, H., (2019). Pain reduction after photoablation. EyeWiki by the American Academy of Ophthalmology. Topical NSAIDs are used to treat invasive corneal tissue damage. There is a risk of corneal damage such as choking, loss, delayed corneal epithelial healing, or corneal lysis (which can lead to vision loss). When soft bandage contact lenses are used, this method can stimulate epithelial cell regrowth and can act as a delivery system for antibiotics or topical NSAIDs. However, the bandage... Diaphragmatic contact lenses can promote bacterial growth and are often ineffective in reducing pain. Shetty, R., et al., Pain management after photorefractive keratectomy, Journal of Cataract Refract Surgery, 45(7):972-976 (2019).

[0012] Acute eye pain can also be treated with topical ophthalmic anesthetic drops, such as propalacaine hydrochloride and tetracaine hydrochloride. These aqueous solutions are given as short-term treatment for pain, or when measuring intraocular pressure, removing foreign bodies, relaxing corneal sutures, or as preoperative anesthetics for eye surgery. Local anesthetics are administered at a dose of approximately 15-20 For a few minutes, it may block the corneal nerves from sending pain signals. While this short-term pain relief may necessitate continued application, chronic use can ultimately lead to corneal toxicity. The toxic effects on the cornea include damage to interstitial corneal stromal cells, which play a crucial role in the healing of corneal trauma. If epithelial cells are unable to migrate across the cornea, the epithelium will eventually begin to slough off, resulting in chronically non-healing of the corneal epithelium.

[0013] However, retaining some pain sensation is important for the normal function of a healthy cornea. Neuropathic keratopathy, also known as neurotrophic keratitis, is a syndrome in which the surface of the eye experiences a progression from tear film abnormalities to epitheliopathy and ultimately to interstitial lysis due to pathological defects in the sensation of the cornea and conjunctiva. In true neuropathic keratopathy, the eye should have corneal and conjunctival sensory defects due to pathological destruction of the trigeminal nerve, which can result from surgery intended to treat trigeminal neuralgia, surgery for acoustic neuroma, or infections such as herpes zoster ophthalmicus or leprosy. Other forms of neuropathic keratopathy result from the misuse of local anesthesia. In rabbit models, typical trophic changes in the corneal epithelium have been shown after controlled thermal coagulation of the trigeminal ganglion in rabbits. This denervation has been found to significantly affect the proliferative activity of the epithelium, resulting in poor mitosis.

[0014] As described above, the cornea is highly sensitive to pain or discomfort. There are many human clinical conditions that cause mild to severe corneal pain and discomfort, all of which could potentially be addressed by the development of safe and effective treatments for corneal pain. The current state of focal palsy droplets only paralyzes the cornea for a few minutes, while chronic use can lead to severe pathological conditions such as corneal infection and corneal lysis. Furthermore, conventional approaches to treating eye pain result in complete loss of sensation to the eye, which can be very problematic in chronic situations due to the risk of developing neuropathic keratopathy. Moreover, in chronically inflamed and painful eyes, corneal somatic sensory dysfunction becomes a dominant feature of pain syndromes. In summary, there are many patients who have weakening eye surface discomfort that can persist long after the original injury, either associated with active corneal pathology or without detectable progressive pathology. Clearly, there is a great, yet unaddressed, clinical need for the development of safer, longer-acting corneal anesthesia therapies that partially block corneal sensation and significantly reduce patient discomfort. [Overview of the project]

[0015] overview In one aspect, the present invention provides a method for alleviating symptoms of discomfort on the surface of the eye, the method comprising: applying a cold slurry topically adjacent to the limbus of the cornea of ​​a patient's eye, the cold slurry comprising water and a coagulation point depressant, the topical application of the cold slurry being configured to cause a certain degree of paralysis of the cornea of ​​the eye for a certain period of time, and the ocular sensation of the eye being restored after a certain period of time.

[0016] In some embodiments, the cold slurry is applied posterior to the limbus.

[0017] In some embodiments, the time is longer than about two days, without further application of the cold slurry on any day after the first day of local application.

[0018] In some embodiments, the time is longer than about 7 days, without further local application of the cold slurry on any day after the first day of local application.

[0019] In some embodiments, the freezing point depressant is glycerol.

[0020] In some embodiments, ocular sensation of the eye is restored approximately 21 days after topical application of the cold slurry.

[0021] In some embodiments, the sclera of the patient's eye is cooled to a temperature of approximately -6°C to approximately 4°C during topical application of the cold slurry.

[0022] In some embodiments, the cold slurry is applied locally for approximately 5 to 15 minutes.

[0023] In some embodiments, further amounts of the cold slurry are applied locally again approximately every 90 seconds.

[0024] In some embodiments, the method further includes the step of placing a contact lens in the patient's eye before topically applying the cold slurry.

[0025] In some embodiments, the cold slurry is configured to have paste consistency.

[0026] In another aspect, the present invention provides a method for alleviating symptoms of discomfort on the surface of the eye, the method comprising: placing a protective cover on the cornea of ​​the patient's eye; and applying a cold slurry topically to the conjunctiva of the patient's eye, wherein the topical application of the cold slurry causes an extended reduction of pain in the patient's eye, and partial sensation of the cornea of ​​the patient's eye is maintained during the extended reduction of pain.

[0027] In some embodiments, the cold slurry is applied to the posterior portion of the limbus.

[0028] In some embodiments, the cold slurry is applied to a protective cover.

[0029] In some aspects, the extended pain reduction lasts for more than about 7 days without further application of the cold slurry on any day after the first day of topical application. .

[0030] In some embodiments, the extended pain reduction lasts for about two days or longer without further application of the cold slurry on any day after the first day of topical application. .

[0031] In some embodiments, the extended pain reduction lasts for more than approximately 14 days without further application of the cold slurry on any day after the first day of topical application.

[0032] In some aspects, the symptoms are due to dry eye syndrome or corneal somatosensory dysfunction.

[0033] In some embodiments, the sclera of the patient's eye is cooled to a temperature of approximately -6°C to approximately 4°C during the topical application of the cold slurry.

[0034] In some embodiments, the protective cover is a contact lens, which prevents the cornea of ​​the eye from freezing.

[0035] In another aspect, the present invention provides a method for alleviating symptoms of discomfort on the surface of the eye, the method comprising: administering a cold slurry to the eye of a patient, the cold slurry comprising water and a certain proportion of ice particles, the administration of the cold slurry causing prolonged hypoesthesia of the eye, the ocular sensation of the eye being restored after the prolonged hypoesthesia, and the administration of the cold slurry not causing permanent damage to the cornea of ​​the eye.

[0036] In some embodiments, the present invention further relates to dry eye syndrome, chronic eye pain, postoperative pain, pain after optical corneal refractive surgery, pain after LASIK, pain after cataract surgery, and Pain after recovery from open globe injury, corneal injury, and corneal somatic sensory dysfunction. This includes treating conditions selected from the group consisting of generalized pain, allergic pain, and pain from acute injury.

[0037] In some embodiments, cold slurry is administered by injection.

[0038] In some embodiments, the cold slurry is injected into the subconjunctival space.

[0039] In some embodiments, cold slurry is administered via topical application.

[0040] In some embodiments, the proportion of ice particles is approximately 20% to 40%.

[0041] In some embodiments, the temperature of the cold slurry is approximately -20°C to approximately -5°C.

[0042] In another aspect, the present invention provides a method for alleviating symptoms of discomfort on the surface of the eye, the method comprising: applying a cold slurry topically to or proximal to the ocular surface of a patient's eye, the topical application of the cold slurry causing prolonged corneal hypoesthesia, the ocular sensation of the eye being restored after the prolonged hypoesthesia, and the topical application of the cold slurry not causing permanent damage to the cornea of ​​the eye.

[0043] In some embodiments, the cold slurry is applied to the proximal part of the limbus.

[0044] In some embodiments, prolonged paresthesia lasts longer than approximately one day after a single treatment of topical application of cold slurry.

[0045] In some embodiments, ocular sensation of the eye lasts for approximately 30 days after topical application of the cold slurry. It will recover soon.

[0046] In some embodiments, the cold slurry is applied locally for approximately 5 to 15 minutes. .

[0047] In some embodiments, the method further includes placing a contact lens in the patient's eye before topically applying the cold slurry, the contact lens preventing freezing of the cornea of ​​the eye. [Brief explanation of the drawing]

[0048] Brief explanation of the drawing The following figures illustrate exemplary embodiments of the present invention. [Figure 1] Figure 1 shows freezing point depression graphs for liquid water, a solution containing 10% glycerin volume / volume (v / v), and a solution containing 20% ​​glycerin (v / v). [Figure 2] Figure 2 is a table showing the breakdown by volume and weight of components of an exemplary biomaterial that can form an injectable cold slurry. [Figure 3] Figure 3 is a graph characterizing the ice content of cold slurries with crystallization set points of -5.5°C and -8.1°C. [Figure 4A] Figure 4 shows a diagram of the human eye, illustrating the degrees of different regions of the eye (4A) and anatomical reference (4B). [Figure 4B] Figure 4 shows a diagram of the human eye, illustrating the degrees of different regions of the eye (4A) and anatomical reference (4B). [Figure 5] Figure 5 is a graph showing real-time scleral temperature monitoring in rabbits after administration of topically applied cold slurry (solid line) and injected cold slurry (dashed line) into the eye. [Figure 6] Figure 6 is a graph showing the time course of sensory decline in rabbit eyes after administration of injected cold slurry (diamond shape), topically applied cold slurry (triangle shape), and slurry topically applied at room temperature (square shape) to eyes with exposed corneas. [Figure 7] Figure 7 is a graph showing the time course of sensory decline in rabbit eyes after topical application of a cold slurry to eyes that do not expose the cornea. [Figure 8] Figure 8 shows fluorescently stained rabbit corneas illustrating corneal healing over time, following intentional 8 mm corneal detachment (8A) and local application of cold slurry (8B) as control groups. [Figure 9] Figure 9 is a graph showing the time course of sensory impairment in the eyes of six rabbits after a combination therapy in which a cold slurry was first applied topically and then injected. In three rabbits (indicated by diamonds, squares, and triangles), the injected slurry did not contain liposomes, while in the other three rabbits (indicated by "X", stars, and circles), the injected slurry did contain liposomes. [Modes for carrying out the invention]

[0049] Detailed explanation This disclosure describes apparatus, devices, systems and methods for treating eye surface discomfort using biological materials, such as cold slurries. In some embodiments, the biological material is used in human patients or subjects (e.g., for preventive or therapeutic purposes to reduce eye discomfort) Delivered to the eyes of a non-patient human or non-human animal (via topical application or injection). This is a cold slurry (e.g., ice slurry). The systems and methods disclosed herein provide unexpectedly prolonged ocular hypoesthesia. The hypoesthesia can result in the restoration of ocular sensation within days or weeks after application of the cold slurry treatment, without causing prolonged corneal paralysis, subsequent permanent damage to the cornea, or disrupting the progression of corneal healing.

[0050] In some embodiments, a cold slurry may be applied topically to achieve a desired therapeutic effect, such as improving or treating discomfort on the surface of the eye due to prolonged corneal paralysis. In some embodiments, a therapeutically effective cold slurry is composed entirely of water and excipient materials (i.e., materials without active pharmaceutical compounds). In other embodiments, the cold slurry further contains known active pharmaceutical compounds. In some embodiments, a protective layer, such as a contact lens, is applied to the cornea before topical application of the slurry. In some embodiments, the eyelids are protected from topical application of the slurry by inserting a speculum made of plastic or other thermally nonconductive material into the subject's eye.

[0051] In some embodiments, the length of time the slurry is applied to the subject's eye may be varied to induce greater or more gradual paresthesia. In some embodiments, the temperature of the slurry applied to or injected into the subject's eye may be varied to induce greater or more gradual paresthesia. In some embodiments, the paresthesia decreases over time until it is no longer noticeable. In other embodiments, greater paresthesia is induced to paralyze more of the nerves in the subject's eye, especially if the subject's eye may be particularly sensitive.

[0052] In some embodiments, containers containing biomaterials (e.g., vials, syringes) are accepted for clinical management. The biomaterials may be accepted in a crystalline (or partially crystalline) state. In some embodiments, they can be administered to human patients or subjects (e.g., patients) via topical application or injection. The final product administered to humans or non-human animals (who are not human) is sterile ice particles of water and modified It is a cold slurry composed of dynamic excipients or additives, such as freezing point depressants. For example, the percentage of ice particles in the cold slurry is less than about 10% by weight of the slurry. The ice particles can be composed of approximately 10% to 20% by weight, approximately 20% to 30% by weight, approximately 30% to 40% by weight, approximately 40% to 60% by weight, and more than approximately 60% by weight. The size of the ice particles is described in U.S. Patent Application No. 15 / 505,042 (Publication No. US2017 / 0274011), which is incorporated herein by reference, and is varied. It allows for fluidity to pass through containers of various sizes (for example, needle gauge sizes from approximately 7 to 43). It is controlled accordingly. Furthermore, the size of the ice particles can be conditioned using other methods to allow fluidity through containers of various sizes. In some embodiments, the majority of the ice particles have a diameter that is less than about half the inner diameter of the lumen or container used for injection. For example, the ice particles may be about 1.5 mm or less in diameter for use in a 3 mm catheter.

[0053] There are various techniques that can be used to prepare cold slurries. This disclosure is not limited to any particular method or technique.

[0054] In some embodiments, one or more excipients may be included in the cold slurry. Excipients It is not a therapeutic agent in itself, but also a diluent, adjuvant, and / or a subject of the therapeutic agent. or any substance used as a vehicle for delivery to a patient, and / or These are substances added to compositions to improve handling, stability, or storage properties. Excipients are present in concentrations of less than approximately 10% of the volume / volume (v / v) of the cold slurry, and approximately 10% v / v to approximately 20% v / v of the slurry. It can constitute approximately 20% v / v to 30% v / v, approximately 30% v / v to 40% v / v, and more than 40% v / v. Various added excipients alter the phase change temperature of the cold slurry (e.g., the freezing point). To reduce the viscosity of the cold slurry, the proportion of ice in the cold slurry is changed. To change this, and to prevent the aggregation of ice particles, dendritic ice formation (i.e., seen in snowflakes) occurs. To prevent the formation of multiple branched "dendritic" crystals, the separated ice particles It may be used to maintain, increase the thermal conductivity of the fluid phase, or improve the overall prophylactic, therapeutic, or anesthetic effect of the cold slurry.

[0055] One or more freezing point depressants may be added as excipients to form a cold slurry having a freezing point below 0°C. By lowering the freezing point of the slurry, the slurry retains its fluidity and remains injectable while still containing an effective proportion of ice particles. As a free-point depressant, salts (e.g., sodium chloride, betadex sulfobutyl ether) are used. Thorium), ions, lactated Ringer's solution, sugars (e.g., glucose, sorbitol, mannitol, heta starch, sucrose, (2-hydroxypropyl)-β-cyclodextrin or combinations thereof), biocompatible surfactants, such as glycerol (also known as glycerin or glycerine), and other polyols (e.g., polyvinyl Examples include alcohols (polyethylene glycol 300, polyethylene glycol 400, propylene glycol), other sugar alcohols, or urea. Other exemplary coagulation point depressants include This is disclosed in U.S. Patent Application No. 15 / 505,042 (Publication No. US2017 / 0274011), which is incorporated herein by reference in whole. In other embodiments, having the consistency of toothpaste, A slurry paste with a viscosity ideal for local application is formed.

[0056] The concentration of the freezing point depressant determines the proportion of ice particles in the cold slurry, as well as its fluidity and injectability. The degree of freezing point reduction is determined by U.S. Patent Application No. 15 / 505,042 (as incorporated herein). The following formula is found in publication number US2017 / 0274011): ΔTF = KFbi It can be calculated using the formula, where ΔTF is the freezing point depression (defined by TF (pure solvent) - TF (solution)), KF is the freezing point depression constant, b is the molar concentration, and i is the individual solute concentration. This is the van't Hoff coefficient, which represents the number of ionic particles per molecule. Other methods for calculating the freezing point depression may also be used, as disclosed in U.S. Patent Application No. 15 / 505,042 (Publication No. US2017 / 0274011).

[0057] Referring to Figure 1, graphs of freezing point reduction are shown for pure water T1, a mixture of water and 10% (v / v) glycerin T2, and a mixture of water and 20% (v / v) glycerin T3. In this experiment, all substances were placed in a freezer maintaining a constant temperature of -20°C. The temperature was measured using a thermometer placed inside the solution. The graph shows that the mixture of water and glycerin has a different freezing point than pure water, indicating that the solution can be cooled to below 0°C. This means that crystallization can occur only partially. The graph shows that, upon cooling, pure water T1 is at a normal temperature of 0°C. This indicates that crystallization occurs at the supercooling point. This is shown by the time the pure water remains at a temperature of approximately 0°C, from approximately 1.3 hours to approximately 4.4 hours, starting immediately after the pure water T1 passes its supercooling point of approximately -6°C. It is possible that it has an equilibrium window for crystallization (i.e., the "flat straight line" portion of pure water T1 in Figure 1). This is typical for pure solvents. Regarding a 10% glycerol solution T2, cooling the solution... Crystallization begins at the first freezing point of approximately -3°C after about 2.2 hours, and continues as the solution temperature further decreases to approximately -8°C after about 6 hours. The initial crystallization occurs immediately after the 10% glycerin solution T2 passes its supercooling point of approximately -8°C (which may vary from sample to sample, e.g., a supercooling point of approximately -15°C to approximately -3°C) at about 2.2 hours. Having a temperature window for crystallization descent for the 10% glycerin solution T2 is typical for solutions (i.e., impure mixtures). Similarly, for the 20% glycerin solution T3, cooling causes the solution to begin crystallization at the first freezing point of approximately -7°C after about 3.5 hours (which may vary from sample to sample, e.g., after the first supercooling point of approximately -25°C to approximately -5°C). Initially, the solution temperature dropped further to approximately -11°C after about 6 hours, and then continued to decrease after another 6.5 hours. As the solution continues to cool, crystallization persists. The initial crystallization occurs immediately after the 20% glycerin solution T3 passes its supercooling point of approximately -14°C, which is indicated at about 3.5 hours. Similar to the trace for the 10% glycerin solution T2, the temperature window for crystallization of the 20% glycerin solution T3 is relative to the solution. This is typical.

[0058] Referring to Figure 2, this chart shows exemplary biomaterials that can form cold slurries. The components are shown. This chart shows that the proportion of ice for an exemplary biomaterial can be calculated for a given temperature. The exemplary slurry contains 30% by mass of ice (w / w) at -10°C. This exemplary slurry contains 80 mL of saline solution (0.9% NaCl) and 20 mL of glycerin. It has rolls (i.e., glycerin). By weight, such slurry is approximately 79.6g of pure water, approximately 0 It has 0.72 g of sodium chloride and approximately 25.2 g of glycerol (about 20% v / v). In other embodiments, the slurry may contain a higher or lower percentage of glycerol by adjusting the relative volume of glycerol to the saline solution. For example, other suitable slurries contain about 10% glycerol (v / v), about 10% to about 20% glycerol, about 30% glycerol or more than about 30% glycerol. Thus, when the active pharmaceutical compound is added to the slurry the concentration of the saline solution can be adjusted to maintain the excipient at the desired concentration, such as glycerol. The proportion of ice varies depending on the composition of the biological material.

[0059] Referring to FIG. 3, different slurry compositions (batches) are characterized with respect to their temperature profiles and ice content. Different slurry batches were placed on a copper plate having a thermocouple wire heated to 40° C. to measure the change in temperature of the slurry over time. The plotted data shows the change in temperature over time for three different slurry batches. The temperature is measured at two different positions for each slurry: inside the copper plate (traces A B C and C C ) and in the middle of the copper plate exposed to the outside of the plate (traces A C B M and C M ). The temperature traces show three separately made slurry batches: the slurry composition with 15% glycerin (having a temperature condensation temperature (setpoint) of -8.1° C.) is represented by traces A M and A C , and two different slurry batches with 10% glycerin each (having a temperature condensation temperature of -5.5° C.) are traces B M and B as well as traces C C and C M and C C and C MIt is represented as follows: When the slurry batch is first introduced onto the copper plate, the thermocouple wires embedded inside the plate (trace A) C B C and C C ) First, the heated plate (for example, trace A at time 0) C The warm temperature (31°C) was measured, and then introduced... For the cooling effect of the slurry, a lower temperature (e.g., trace A for about 2 minutes) is required. C Equilibrium is reached at 22°C. On the other hand, for the thermocouple wire placed in the middle of the plate, the slurry -When the slurry is first introduced onto the copper plate, the wire is exposed, so the slurry immediately comes into contact with the thermocouple wire. This is because the crystallized slurry in contact with the wire initially has a negative temperature reading at an intermediate position (e.g., trace A at time 0). M (Regarding -5°C), then when the slurry begins to melt on the heated plate, it reaches a warmer temperature (e.g., trace A in about 4 minutes). M Equilibrium is brought about at 18°C. Thermocouple wires (trace A) exposed on the outside of the plate. M B M and C M Using (), a phase transition can be detected while the crystallized slurry begins to melt. The graph shows that two slurry compositions with 10% glycerin react at similar points (Trace B). M About 4 minutes, and trace C M (Approximately 2.7 minutes), 15% Phase transition in glycerin slurry (the phase transition is trace A) M (This happens in about 0.2 minutes) The graph shows that they reach different phase transitions. The graph also shows the same composition (10% glycerin: trace B). C and B M and trace C C and C MTwo slurry batches with different compositions (15% glycerin: trace A) reach equilibrium within a similar timeframe and at similar temperatures of approximately 15°C to 19°C, depending on the thermocouple position (middle / bottom) (when measured by the positions of two thermocouple wires). On the other hand, two slurry batches with different compositions (15% glycerin: trace A) C and A M The slurry with ) has a different temperature profile from the other two, and depending on the position of the thermocouple (middle / bottom), it reaches equilibrium more quickly at a temperature of approximately 19°C to 22°C. Therefore, Figure 3 shows that slurries of different compositions have different temperature profiles, and the same composition Consistency exists in each batch across slurries containing (for example, B C and B M Slurry and C C and C M The slurry represented by A C and A M (Having a similar temperature profile but different from the temperature profile of the slurry represented) This indicates that.

[0060] Referring to Figure 4A, a diagram of the eye is shown, illustrating the scleral zone 2, scleral zone 3, cornea 1, and limbus (showing the dotted line between cornea 1 and scleral zone 2). Figure 4A is from Andreoli CM, Gardiner MF. Open globe injuries: Emergent evaluation and initial management. Reproduced from: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Figure 4B shows a diagram of an eye with superimposed protractors indicating angles in degrees (°) relative to the eye. In this diagram, 90° represents the highest position along the eye.

[0061] In some embodiments, the cold slurry described herein may be applied topically or, alternatively, injected to achieve long-lasting hypoesthesia that reduces discomfort on the surface of the eye. Hypoesthesia refers to a reduction in eye discomfort or pain without complete blockage of sensation in the eye. Hypoesthesia is thus distinguished from ocular paralysis, which is characterized by a more pronounced blockage of sensation in the eye. Hypoesthesia may include corneal paralysis, which causes a reduction in the pain response while maintaining normal eye function, including otherwise normal healing processes. Ocular paralysis, on the other hand, can cause abnormal eye function because all corneal sensation is lost. Corneal sensation is important for normal eye function, such as blinking and the initiation of protective mechanisms, such as tear production.

[0062] One approach is to apply droplets of cold slurry to the surface of the eye, with a volume that can vary from 1 to 100 microliters, preferably about 10 to 80 microliters. The formulation can then be administered directly to the surface of the eye. Alternatively, the cornea may be rubbed first, followed by the administration of the droplets. In some embodiments, topically applied cold slurry has a more fluid paste consistency, and larger amounts can be applied topically to the surface of the eye as a treatment (3-50 ml).

[0063] In some embodiments, the cold slurry described herein is applied locally to the posterior limbus of the cornea, for example, the region shown as scleral zone 2 in Figure 4A, for a period of about 1 to 20 minutes. In some embodiments, the cold slurry is applied for a period of about 5 to 10 minutes. In several embodiments, the cold slurry is administered to each eye every 1 to 10 seconds over a period of 1 to 20 minutes. This treatment could be repeated several times over short periods (e.g., 5 to 20 minutes). In one embodiment, the cold slurry is applied locally to the posterior limbus of the cornea for approximately 10 minutes, with fresh slurry being applied again every 90 seconds until 10 minutes have been reached.

[0064] In some embodiments, during topical application, sensitive ocular structures are protected from contact with the cold slurry to limit potential side effects. Protection of the corneal surface may limit some or all corneal cell damage or refractive changes resulting from freezing corneal tissue. Protection of the palpebral conjunctiva and eyelids may prevent redness, swelling, and inflammation unrelated to the therapeutic effect. Potential adverse effects on the cornea can be reduced by selectively applying ice to the posterior surface of the eye at the edge of the conjunctival margin (corresponding to the anterior anatomical region known as zone 2, Figure 4A). This can be minimized.

[0065] In some embodiments, protective contact lenses or other protective covers may be applied so as to be positioned on the cornea to protect it from damage. In some embodiments, the corneal cover completely prevents the cold slurry from directly contacting the corneal surface. In some embodiments, a lid speculum is used to keep the eyelid open during topical application of the cold slurry. In some embodiments, the lid speculum is made of a thermally nonconductive material such as plastic or another nonconductive material known in the art. Thermally nonconductive materials may be used in the lid speculum to protect the eyelid (inner and outer) from freezing, which could cause damage to the eyelid during cold slurry treatment. In some embodiments, the cold slurry is applied only to the sclera, and the cornea is protected from freezing. In some embodiments, protecting the cornea from freezing ensures faster corneal healing.

[0066] A device to control the area exposed to cold slurry to only the conjunctiva / sclera of the eye Because it can be used, the cold slurry cannot physically come into contact with or freeze adjacent tissues unrelated to the desired clinical effect. In some embodiments, the cold slurry formulation has no direct contact with the surface of the eye at all. The cold slurry formulation may be contained within a thermally conductive material, such as a small metal or polymeric donut-shaped or other protective ring, thus providing a barrier to direct contact between the formulation and the surface of the eye, but the necessary cooling still occurs. In some embodiments, undesirable side effects (e.g., direct application of a hyperosmotic solution to the eye) may occur. To minimize potential eye irritation, the device uses cooling to reduce the potential therapeutic effect. Directing the device / cooling only to the area prevents it from contacting and affecting adjacent tissue. .

[0067] In some embodiments, the cold slurry described herein is injected as a subconjunctival bolus approximately every two minutes. Each injection provides approximately 0.5–1.5 ml of frozen slurry. It can be administered and repeated approximately every 2 minutes for the desired duration of treatment or a total of approximately 10 minutes. In one embodiment, the cold slurry is injected directly closer to the axon of the ciliary nerve. The ciliary nerve is located at approximately 0° and 180° of the eye (Figure 4B).

[0068] In some embodiments, a standard syringe is used to inject the slurry. Alternatively, a syringe conditioned for the slurry may be used for injection. In some embodiments, the syringe may have a needle of about 18G to about 25G.

[0069] In some embodiments, real-time temperature sensing is performed on the surface of the eye during treatment (e.g., cold slurry injection or topical application). In some embodiments, the cold slurry is used to temperature the tissue (e.g., corneal surface, conjunctiva or any other part of the eye) below approximately 0°C, below approximately -1°C. It is applied to cool to approximately -2°C, approximately -3°C, approximately -4°C, or approximately -5°C. In some embodiments, the cold slurry is applied for approximately 1 minute, preferably for approximately 2 to 10 minutes. The temperature of the cooled tissue and the length of time the slurry is applied may vary to alter the sensory impairment experienced by the subject.

[0070] In some embodiments, the cold slurry is periodically re-administered to the subject's eye over time to maintain the therapeutic effect. A range of options for local administration and / or injection are available. There are possible frequencies. For example, treatment may be administered at one of the following intervals: once every two weeks; once a month; once every two months; once every three months, etc.

[0071] In some embodiments, cold slurry is used as a safe treatment for corneal palsy to treat corneal discomfort or pain. Various formulations of cold slurry can be used by methods described herein, such as those described above. Further specific embodiments of cold slurry are described with reference to Figures 5-9. "ECT-4143" is a slurry formulation containing 15% glycerol, 30% L-α-phosphatidylcholine liposomes and 0.9% saline (or phosphate-buffered saline). In some embodiments, ECT-4143 is used at a temperature of approximately -25°C to -10°C ( It is administered to the eye (topically or by injection) at the temperature of the slurry. ECT-4143 is administered into the eye (locally or by injection) at a temperature of approximately -18°C (the temperature of the slurry, such as in the embodiments described below, referring to Figures 5-9). ECT-4143 is administered at a rate of approximately 2-3 ml per application, every 90 seconds, until a total treatment time of 10 minutes is reached.

[0072] "ECT-1719" contains 15% glycerol and 0.9% saline (or phosphate-buffered saline). It is a slurry formulation. In some embodiments, ECT-1719 is administered to the eye (topically or by injection) at a temperature of approximately -20°C to -5°C or approximately -15°C to approximately -10°C (slurry temperature). In some embodiments, ECT-1719 is administered to the eye (topically or by injection) at a temperature of approximately -11°C (the temperature of the slurry, such as in the embodiments described below with reference to Figures 5-9). In some embodiments, ECT-1719 is administered by injection at a volume of 0.7 ml per injection, four times. The total injection volume will be 2.8 ml. ECT-1719 is administered approximately every 120 seconds until a total treatment of 10 minutes is reached.

[0073] Referring to Figure 5, the eyes of one rabbit treated topically with cold slurry (ECT-4143, solid line) and a second rabbit treated with cold slurry (ECT-1719, dashed line). Real-time scleral temperature monitoring was performed in rabbits after administration. The ring has a 25g needle containing a temperature probe at its distal end, placed in the subtenon space. This is achieved by inserting a urea. As can be seen in Figure 5, cold urea is injected. The scleral temperature of rabbits treated with Larry (ECT-1719) fluctuated between approximately 0°C and 8°C throughout the duration of the procedure (approximately 0 seconds after cold slurry injection to approximately 463 seconds after cold slurry injection). The sharp line in the graph indicates the end of the test and removal of the temperature probe from the eye tissue after 7.5 minutes. The study showed that the scleral temperature of rabbits treated with locally applied cold slurry (ECT-4143) was lower than that of injected cold slurry, with fluctuations of approximately -6°C to 4°C for most of the time during which temperature was recorded (approximately 0 seconds after local application to approximately 600 seconds after local application). After use, the temperature of the sclera decreased from approximately 4°C during the application time (approximately 0 seconds in Figure 5) to approximately 0°C after approximately 120 seconds. Continued. After the initial period of scleral cooling, the temperature remained relatively stable at approximately 0°C to -5°C from approximately 120 seconds after local application to approximately 520 seconds after local application. Furthermore, from approximately 220 seconds to approximately 520 seconds after local application During the duration of treatment, the scleral temperature showed very little variability and remained stable at approximately -2°C to -3°C. Approximately 620 seconds after local application, the treatment was terminated and the temperature probe was removed, showing a sharp increase in the measured temperature as shown in Figure 5.

[0074] The effect of decreased sensation after cold slurry treatment is measured using a monofilament / sensory meter in the eye. It is measured as a response to tactile stimulation. Starting with a 6 cm filament length, the length is gradually decreased by 0.5 cm increments, and the eye is examined three times at each length until a blink response is induced. As the filament shortens, it becomes stiffer, so higher pressure is applied to the eye when examining it. Perceptual decline at each point in time is based on a given length of monofilament. At each point in time, the length of the specific monofilament recorded is the shortest length (highest pressure) at which there is no blink response. For example, with the longest monofilament at 6 cm... If the rabbit does not blink when you start the survey, then the next monofilament is 5.5 cm long. Examine the eyes using a tweezers. If the rabbit does not blink again, use the next monofilament 5 cm away. Use the length of the blink. If the rabbit blinks here, this means there was no blink response ( Since it reflects the degree of sensory impairment, the previous length of 5.5 cm is recorded as it is the shortest length. The deepest level of sensory impairment was investigated using the shortest filament length (e.g., 0.5 cm). This refers to cases where the rabbit does not blink. A degree of sensory impairment (no pain blockage / no paralysis) is when the rabbit blinks when investigated using the longest filament length (e.g., 6 cm). It is of this nature. The filament length is due to pressure (g / mm²). 2 ) can be converted, and 6cm filament is 0.4g / mm 2It generates pressure (minimum pressure), while the 0.5cm filament is 15.9g / mm². 2 This generates pressure (maximum pressure). Therefore, the recorded pressure corresponds to the shortest filament length for which there is no blinking response.

[0075] Referring to Figure 6, the sensory impairment effect (the degree of corneal paralysis measured using contact stimuli as described herein) was observed in rabbits when cold injections were administered to the eyes with exposed corneas. Slurry (ECT-1719, 3 rabbits in this group, shown as diamonds), locally applied Golds slurry (ECT-4143, 3 rabbits in this group, indicated by triangles) and local treatment at room temperature After administration of the target slurry (ECT-4143, one rabbit in this group, shown as a square) Measurements were taken over time. In Figure 6, the degree of sensory impairment is measured at the highest possible pressure (i.e., 15.9 g / mm²). 2 Recorded for the shortest monofilament used (0.5 cm) corresponding to the pressure. It is expressed as a percentage of pressure (based on the shortest monofilament with a lack of blink response). The degree of sensory impairment is shown on days 1, 7, 14, and 28 after cold slurry administration. For the cold slurry injected (ECT-1719, shown in diamond shape), 1 The sensory impairment effect on day 1 was approximately 20%, and by day 14 it reached baseline levels and gradually improved. It continued to decrease (the error bar overlaps with 0%). Locally applied cold slurry (suitable at 18°C) Regarding the ECT-4143 used (indicated by a triangle), the sensory reduction effect on day 1 was 100% (measured). (Maximum corneal palsy), then gradually decreasing and ending on the 28th day, during which time the pain response... For a slurry (ECT-4143, shown as a square) applied topically at room temperature, the sensory impairment effect returned to baseline levels (error bars overlap with 0%) at any point after treatment. However, this could not be observed. Therefore, Figure 6 shows the unexpectedly strong hypoesthesia effect of locally applied cold slurry, which produced prolonged hypoesthesia (approximately one month). Injected cold slurry produced moderate hypoesthesia, which also lasted longer than expected (e.g., about one to two weeks). Importantly, for both local and injectable methods, cold slurry treatment produced prolonged hypoesthesia that normalized back to baseline levels without causing permanent numbing effects.

[0076] Figure 7 shows the results after administering a topically applied cold slurry (6 rabbits, ECT-4143) to the eyes of rabbits, similar to Figure 6, except that the cornea was not exposed (protected by a contact lens). It exhibits a temporally decreasing effect of perception. The decreasing effect of perception is the same as that described above with respect to Figure 6. The method was used to measure the effect of decreased sensation. The effect of decreased sensation is shown on days 1, 7, 14, 21, and 28 after treatment with locally applied cold slurry. The effect of decreased sensation was approximately 50% on day 1 and gradually decreased, slowly reaching the baseline level by day 21 (error bars overlap with 0%). Therefore, Figure 7 shows that the effect lasted for a long time without causing permanent corneal palsy or any corneal damage. Regarding locally applied cold slurries (with corneal protection) that cause persistent sensory impairment (approximately 3 weeks), they exhibit unexpected moderate to severe sensory impairment effects.

[0077] Referring to Figure 8, a typical image of a rabbit cornea using fluorescein staining is shown as a control. This shows the time course of corneal healing after intentional 8mm corneal detachment, applied to both the group (Figure 8A) and the treatment group with local application of cold slurry (Figure 8B) where protection was applied to the cornea and eyelids. The progression of the injury was determined by measuring the size of the injury over time. As can be seen in Figure 8A, corneal healing in the control group (3 rabbits) was 1.31 mm in the first 24 hours after corneal detachment. 2 / hour, and 0.62mm 24 to 60 hours after corneal abrasion. 2This occurred at the average healing rate per hour. Unexpectedly, as shown in Figure 8B, corneal healing was not impaired in rabbits that received topically applied cold slurry (ECT-4143) compared to the control group. In this group (3 rabbits), corneal healing after cold slurry treatment was impaired. 1.09 mm in the first 24 hours 2 / hour, and 0.63 mm 24 to 60 hours after cold slurry treatment. 2 This occurred at the average healing rate per hour.

[0078] Referring to Figure 9, the graph shows the cold slurry being first applied topically and then injected. The combination therapy was followed by a time-dependent reduction in sensory perception in six rabbits. In three rabbits (indicated by diamonds, squares, and triangles), the topically applied cold slurry was ECT-1719, which was the same cold slurry formulation (ECT-1719) administered via injection, but without liposomes. In the other three rabbits (indicated by "X", stars, and circles), the topically applied cold slurry was ECT-1719 (without liposomes), which was again administered via injection of the liposome-containing cold slurry (ECT-4143). The reduction in sensory perception was observed (see Figures 6 and 7). As described herein, the maximum pressure at which the rabbit did not blink is shown. As shown in Figure 9, the desensitizing effect continued to increase after treatment with combination therapy (liposomes or Regardless of whether it was a non-liposomal injection, the peak could be reached somewhere between days 4 and 11. The hypoesthesia effect gradually decreased and returned to baseline levels around day 17. Surprisingly, a second, less pronounced period of hypoesthesia occurred spontaneously around day 22 and returned to baseline levels by day 26. It returned to a slalom level and gradually came to an end.

[0079] The data described herein support the idea that cold slurry (topical and injectable) is a safe, long-term treatment for corneal palsy that produces decreased sensation without permanent corneal palsy or damage.

[0080] Without being bound by theory, the basic premise is that the application of cold slurry stops the signaling of pain stimuli by causing degeneration of the myelin sheath on nerves. Myelin is a fatty substance that rapidly and efficiently moves electrical stimuli towards nerve axons. It is a lipid-rich substance. Administration of a cold slurry over both the free nerve endings and myelinated portions of nerves, the cold temperature, freezes or crystallizes the liquid component of fat cells, inducing apoptosis and denaturing the myelin sheath, a process known as Wallerian degeneration. This process significantly reduces the transmission of pain stimuli by ciliary nerves from the cornea to the brainstem. Because of the thin volume of distal nerve endings on the surface of the eye, not all peripheral nerves are affected, so not all sensation from the surface of the eye is eliminated; this induces relative sensory impairment instead of complete sensory paralysis. Furthermore, the effect recedes after about 4-8 weeks, at which point the sensation in the eye is fully restored. Other options for inducing Wallerian degeneration include radiofrequency ablation and cryoneurolysis (freezing at temperatures reaching -80°C), but these procedures affect the surrounding tissue and This presents a risk of damaging the structure. Furthermore, an inert vehicle containing ice crystals does not harm other components of the eye, making it a reasonable application for treating nerves causing pain on the surface of the eye. This approach preserves vision and the normal function of the surface of the eye.

[0081] Without being bound by any particular theory, injection into the subconjunctival space surrounding the limbus of the cornea causes the cold slurry to distribute around the free nerve endings of the ciliary nerve. There are two major ciliary nerves with free nerve endings that branch into the cornea of ​​both eyes. Each ciliary nerve has its axis The axons are myelinated along the cord and are located downstream from the free nerve endings in the cornea. Injecting the cold slurry spreads to the downstream area where the ciliary nerve axons are myelinated. As cold slurry spreads to the axons of ciliary nerves, it causes crystallization and apoptosis of the myelin sheath, demyelination of the ciliary nerve. Demyelination prevents the nerve from transmitting pain signals to the brain. Alternatively, cold slurry can cause Wallerian degeneration of the nerve, which can also prevent pain signals from being transmitted to the brain.

[0082] Cold slurry, applied topically and / or injected, damages the surface of the cornea. Since it does not involve any adverse reactions, it is more advantageous than other administration methods.

[0083] The systems and methods disclosed herein are not limited to the specific embodiments described herein. In fact, various modifications of devices, systems, and methods beyond those described herein will be apparent to those skilled in the art from the foregoing description. [Examples]

[0084] Example 1 - In vivo trial of cold slurry treatment for corneal palsy The results of the tests described in this example can be seen in Figures 5-9. Preclinical studies using animals were conducted to determine the efficacy of the treatment, including the best means of delivering the treatment, the duration of the treatment's effect, and any potential side effects. For ocular studies, the New Zealand white rabbit is an ideal model because its cornea and corneal innervation system are very similar to those of humans, and it is a standard, accepted model for corneal studies in the literature.

[0085] Procedure preparation The animals were given pre-anesthetic (rabbit xylazine 1.1 mg / kg IM, buprenorphine HCl 0.01-0.05 mg / kg IM) and pre-surgical antibiotic (cefazolin 25-50 mg / kg IM). The animals were then anesthetized. The animals were intoxicated (rabbit ketamine 33 mg / kg IM). The animals were placed on a heating pad and vital signs were monitored. Two drops of 0.5% proparacaine HCl and 5% phenylephrine / 0.5% tropicamide (expanded droplets) were administered to the eye to be tested. The animals were subjected to inhalation anesthesia with oxygen supplementation (1.5-2% concentration). It was used for sophuran.

[0086] Test Procedure Prepare the animals and administer povidone-iodide droplets to the surface of the eyes in the usual sterile manner. Place the eyelid retractor in place and cover it with a sterile cloth. Then, inject the slurry locally or subconjunctivally.

[0087] Injection To evaluate the sensory impairment ability of ECT-1719, approximately 0.7 mL of cold slurry was administered to the limbus of the cornea. It was injected into the subconjunctival space around the limbus. Due to partial pressure from the cornea, the force of the injection, and the presence of the natural potential space, the injected cold slurry was uniformly distributed 360° around the limbus. The injection procedure is repeated every 120 seconds for a total of 10 minutes.

[0088] The control animals were treated with sterile saline (control) or with a vehicle control (cooled (A slurry was administered.) At the end of the procedure, the eyes were carefully examined and the eyelid retractor was removed. The sterile cloth was removed, and the eye was rinsed with sterile saline solution. A further control group was provided with conventional anesthetic droplets applied to the cornea. All surgical procedures were performed on the left eye only (for control purposes) and lasted approximately 10 minutes.

[0089] The surgical procedure described above involves various different medications (e.g., steroids, antibiotics) depending on the condition. This is commonly done in humans using injections (etc.).

[0090] Local administration To evaluate the ECT-4143 sensory impairment capacity, the slurry was applied topically to the posterior margin of the corneal surface of the eye. The cornea was protected with a contact lens, and the eyelids with a plastic eyelid retractor. Approximately 2-3 ml of cold slurry was applied per application, approximately every 90 seconds, for a total of 10 minutes. It was applied topically until the treatment time was reached. At the end of the procedure, the eye was carefully examined and opened. The eyelid apparatus was removed, the sterile cloth was removed, and the eye was washed with sterile saline solution.

[0091] Post-procedures for surviving animals Neomycin / polymyxin / bacitracin ophthalmic ointment, and a few drops of prednisone acetate were applied to the operated eye after surgery. The animals were removed from the operating table and placed on a heating pad. While awaiting recovery, the animals were monitored for vital signs (e.g., heart rate, respiration). (SpO2). The animals were monitored until muscle control was restored. They were returned to their original cages.

[0092] Post-surgical animal monitoring The animals undergo a comprehensive eye exam one day after surgery, followed by weekly corneal sensation tests. Measurements were taken. If a beneficial decrease in intraocular pressure was observed in animals treated with this therapy, intraocular pressure was also measured. Furthermore, a slit lamp examination using fluorescein staining and a dilated fundus examination (i.e., dilating the eye with 5% phenylephrine and 0.5% tropicamide) were performed. The animals were placed in a confined cage for a few seconds while the eye drops were administered drop by drop.

[0093] Effects of administration The effects of administering cold slurry were tested using several techniques.

[0094] The paralyzing effect of a cold slurry was tested using a sensory meter. A filament of a specific stiffness was extended from the device. Animals treated with the cold slurry were able to withstand a stronger force from the sensory meter than animals in the control group. This was indicated by whether the animals atrophied when their eyes were poked with the sensory meter filament. The test was performed multiple times over the course of the study to determine the duration of the paralyzing effect.

[0095] The effect of cold slurry on the eye's healing ability was also tested. Epithelial defects were created in the cornea using trephin and a corneal brush. The wounds were examined and photodocumented using fluorescein staining. The size of the wounds was measured and the progression of the wounds was observed using control stains. The rows were measured. Cold slurries did not affect the eye's healing ability. The following are examples of aspects of the present invention. Item 1 A method for alleviating symptoms of discomfort on the surface of the eye, comprising the step of locally applying a cold slurry adjacent to the limbus of the cornea of ​​a patient's eye, The cold slurry contains water and a freezing point depressant. The topical application of the cold slurry is configured to cause a certain degree of paralysis of the cornea of ​​the eye for a period of time. Ocular sensation in the eye is restored after a certain period of time. method. Section 2 The method according to item 1, wherein the cold slurry is applied to the posterior part of the limbus. Section 3 If there is a certain period, then apply the cold slurry to the local area for an additional time on any day after the first day of local application. The method described in item 1, for a period longer than approximately 7 days, without being applied locally. Section 4 The method described in item 3, wherein the coagulation point depressant is glycerol. Section 5 The method described in item 1, wherein ocular sensation of the eye is restored approximately 21 days after topical application of the cold slurry. Section 6 The sclera of the patient's eye is cooled to a temperature of approximately -6°C to approximately 4°C during the topical application of the cold slurry. The method described in item 1. Section 7 The method described in item 1, wherein the cold slurry is applied locally for approximately 5 to 15 minutes. Section 8 The method according to item 7, wherein an additional amount of cold slurry is applied locally again approximately every 90 seconds. Section 9 The method according to item 1, further comprising the step of placing a contact lens in the patient's eye before topically applying the cold slurry. Section 10 The method according to item 1, wherein the cold slurry is configured to have a paste consistency. Section 11 The process of placing a protective cover on the cornea of ​​the patient's eye; and A method for alleviating symptoms of discomfort on the surface of the eye, comprising the step of applying a cold slurry topically to the conjunctiva of the eye of a patient, Topical application of cold slurry resulted in an extended reduction in the patient's eye pain. Partial sensation in the cornea of ​​the patient's eye is maintained during the prolonged reduction of pain. method. Section 12 The method according to item 11, wherein the cold slurry is applied to the posterior part of the limbus. Section 13 The method according to item 11, wherein the cold slurry is applied on top of the protective cover. Section 14 The method according to paragraph 11, wherein the extended reduction of pain lasts for more than about 7 days without further application of the cold slurry at any time on any day after the first day of topical application. Item 15 The method according to paragraph 14, wherein the extended reduction of pain lasts for longer than about 14 days without further topical application of the cold slurry for any time on any day after the first day of topical application. The method according to paragraph 11, wherein the symptoms are due to dry eye syndrome or corneal somatosensory dysfunction. Section 17 The sclera of the patient's eye cools to a temperature of approximately -6°C to approximately 4°C during the topical application of the cold slurry. The method described in item 11. Section 18 The method described in paragraph 11, wherein the protective cover is a contact lens, and the contact lens prevents the cornea of ​​the eye from freezing. Section 19 A method for relieving symptoms of discomfort on the surface of the eye, comprising the step of administering a cold slurry to the eye of a patient, The cold slurry contains water and a certain proportion of ice particles. Administration of cold slurry causes prolonged ocular hypoesthesia. Ocular sensation of the eye is restored after prolonged paresthesia. The administration of the cold slurry does not cause permanent damage to the cornea of ​​the eye. method. Item 20 The method according to paragraph 19, further comprising a step of treating a condition selected from the group consisting of dry eye syndrome, chronic eye pain, postoperative pain, pain after optical corneal refractive surgery, pain after LASIK, pain after cataract surgery, and pain after repair of open globe injury, post-corneal injury, corneal somatosensory dysfunction, allodynia, and pain from acute injury. Section 21 The method described in paragraph 19, wherein the cold slurry is administered by injection. Section 22 The method described in paragraph 19, wherein the cold slurry is injected into the subconjunctival space. Section 23 The method according to paragraph 19, wherein the cold slurry is administered via topical application. Section 24 The method described in item 19, wherein the proportion of ice particles is approximately 20% to 40%. Section 25 The method described in item 19, wherein the temperature of the cold slurry is approximately -20°C to approximately -5°C. Section 26 A method for alleviating symptoms of discomfort on the surface of the eye, comprising the step of applying a cold slurry topically to or proximal to the ocular surface of a patient's eye, Topical application of cold slurry causes prolonged corneal desensitization. Ocular sensation of the eye is restored after prolonged paresthesia. Topical application of cold slurry does not cause permanent damage to the cornea of ​​the eye. method. Section 27 The method according to item 26, wherein the cold slurry is applied to the proximal part of the limbus. Section 28 Prolonged sensory impairment lasts for more than approximately one day after a single treatment of topical application of cold slurry. The method described in paragraph 26, which continues. Section 29 The method described in paragraph 26, wherein ocular sensation of the eye is restored within approximately 30 days after topical application of the cold slurry. Item 30 The method described in paragraph 26, wherein the cold slurry is applied locally for a period of approximately 5 to 15 minutes. Section 31 A method according to paragraph 26, further comprising the step of placing a contact lens in a patient's eye before topically applying a cold slurry, wherein the contact lens prevents freezing of the cornea of ​​the eye.

Claims

1. A cold slurry formulation for use in a device in a method for relieving symptoms of discomfort on the surface of the eye, The cold slurry contains water and a freezing point depressant. The device includes a thermally conductive material, The method includes the step of applying a thermally conductive material of a device containing a cold slurry formulation to a region adjacent to the limbus of the patient's eye. The application of the device is configured to cause a certain degree of decreased eye sensation for a certain period of time. Ocular sensation in the eye recovers after a certain period of time. Cold slurry formulation.

2. The cold slurry formulation according to claim 1, wherein the thermally conductive material of the device is applied to the posterior portion of the limbus.

3. The cold slurry formulation according to claim 1, wherein the period is a further time on any day after the first day of application, and is longer than about 7 days without locally applying the thermal conductive material of the device.

4. The cold slurry formulation according to claim 3, wherein the coagulation point depressant is glycerol.

5. The cold slurry formulation according to claim 1, wherein ocular sensation of the eye is restored approximately 21 days after application of the thermally conductive material of the device.

6. The cold slurry formulation according to claim 1, wherein the sclera of the patient's eye is cooled to a temperature of about -6°C to about 4°C during the application of the thermally conductive material of the device.

7. The cold slurry formulation according to claim 1, wherein the thermally conductive material of the device is applied locally for about 5 minutes to about 15 minutes.

8. The cold slurry formulation according to claim 7, wherein the thermally conductive material of the device is applied again at intervals of approximately 90 seconds.

9. The cold slurry formulation according to claim 1, further comprising the step of placing a contact lens in a patient's eye before applying a thermally conductive material to the device.

10. The cold slurry formulation according to claim 1, wherein the cold slurry is configured to have a paste consistency.

11. The cold slurry formulation according to claim 1, wherein the thermally conductive material of the device contains a metal.

12. The cold slurry formulation according to claim 1, wherein a certain degree of sensory impairment includes paralysis.

13. The cold slurry formulation according to claim 1, wherein a certain degree of sensory impairment includes a reduction in eye discomfort without complete blockage of ocular sensation.

14. The cold slurry formulation according to claim 1, comprising a degree of sensory impairment while substantially maintaining otherwise normal eye function, including a reduction in pain response.

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